Pemetrexed formulations

ABSTRACT

The present invention is directed to pemetrexed formulations comprising a non-aqueous solvent that remains stable after dilution for at least about 48 hours when stored at 2° C. to 8° C. The present invention is also directed to pemetrexed formulations comprising a non-aqueous solvent that remains stable for at least about 24 months when stored at 2° C. to 8° C.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 15/828,858, filedDec. 1, 2017, which is a continuation of U.S. Ser. No. 15/048,416, nowabandoned, filed Feb. 19, 2016, the disclosure of each of which ishereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Compounds exhibiting anti-folate activity have a well known role aschemotherapeutic agents. One such compound is pemetrexed, which has thechemical name N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid and the structureof formula (1):

Pemetrexed is used in the treatment of pleural mesothelioma andnon-small cell lung cancer. ALIMTA, Eli Lilly's pemetrexed product ispresently supplied in 100 mg and 500 mg vials of lyophilized pemetrexeddisodium for injection. According to the prescribing information, inorder to prepare ALIMTA for infusion the vials are reconstituted insufficient 0.9% Sodium Chloride Injection (preservative free) to give asolution containing 25 mg/mL of ALIMTA. This concentrated solution isthen further diluted into a solution of 0.9% Sodium Chloride Injection(preservative free). The prescribing information cautions thatreconstitution and further dilution is only recommended with 0.9% SodiumChloride Injection (preservative free), and that “ALIMTA is physicallyincompatible with diluents containing calcium, including LactatedRinger's Injection, USP and Ringer's Injection, USP and therefore theseshould not be used.”

Calcium containing diluents, such as Lactated Ringer's Injection andRinger's Injection, are common solutions used in medical settings forthe reconstitution and/or dilution of drug products prior to intravenousadministration. There is a need for pemetrexed dosage forms that arechemically stable after reconstitution and/or dilution with diluentscontaining calcium. In addition to being useful with a wider range ofavailable diluents, the use of such a dosage form would minimize boththe loss of dosage forms due to improper reconstitution or dilution andthe risk that a patient would be administered pemetrexed reconstitutedor diluted in an incompatible diluent.

In solution, pemetrexed undergoes hydrolysis and degrades rapidly. Dueto this rapid degradation, pemetrexed formulations must either belyophilized for long term stability or comprise stabilizers. However,reconstitution of a lyophilized formulation requires multiple steps,each of which increases the risk of user error. In addition,reconstitution of a lyophilized formulation is clinically inconvenientand can take up to 30 minutes.

While stable, ready to use formulations of pemetrexed are known, theyrequire stabilizers, such as anti-oxidants or amino acids as describedin U.S. Pat. No. 6,686,365; CN 101081305; and WO 2012015810, or highlevels of non-aqueous solvents, as described in WO2013144814. It wouldbe advantageous to minimize patient exposure to these additionalingredients.

As such, there is a need for a stable, non-lyophilized pemetrexedcomposition with a minimal amount of additional ingredients. To thisend, we have developed a stable pemetrexed formulation.

SUMMARY OF THE INVENTION

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising pemetrexed and a non-aqueous solvent present at aconcentration less than 0.30 ml/mL, wherein upon dilution with apharmaceutically acceptable diluent to an initial dosage concentrationof pemetrexed, the composition comprises at least 90% of the initialdosage concentration of pemetrexed after storage at a temperature of 2°C. to 8° C. for at least 24 hours.

In further embodiments, the invention is directed to a pharmaceuticalcomposition comprising 25 mg/mL pemetrexed, 250 μL/mL propylene glycol,and water, wherein upon dilution with a pharmaceutically acceptablediluent to an initial dosage concentration of pemetrexed, thecomposition comprises at least 90% of the initial dosage concentrationof pemetrexed after storage at a temperature of 2° C. to 8° C. for atleast 24 hours.

In still further embodiments, the invention is directed to apharmaceutical composition comprising pemetrexed at an initialconcentration of 10 to 50 mg/mL and a non-aqueous solvent present at aconcentration less than 0.30 ml/mL, wherein the composition comprises atleast 90% of the initial pemetrexed concentration after storage at atemperature of 2° C. to 8° C. for at least 12 months.

In further embodiments, the invention is directed to a pharmaceuticalcomposition comprising 25 mg/mL pemetrexed, 250 μL/mL propylene glycol,and water, wherein the composition comprises at least 90% of the initialpemetrexed concentration after storage at a temperature of 2° C. to 8°C. for at least 12 months.

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising pemetrexed and a non-aqueous solvent present at aconcentration less than 0.30 ml/mL, wherein upon dilution with apharmaceutically acceptable diluent to an initial dosage concentrationof pemetrexed, the composition comprises no more than 8% w/w totalimpurities after storage at a temperature of 2° C. to 8° C. for at least24 hours.

In further embodiments, the invention is directed to a pharmaceuticalcomposition comprising 25 mg/mL pemetrexed, 250 μL/mL propylene glycol,and water, wherein upon dilution with a pharmaceutically acceptablediluent to an initial dosage concentration of pemetrexed, thecomposition comprises no more than 8% w/w total impurities after storageat a temperature of 2° C. to 8° C. for at least 24 hours.

In still further embodiments, the invention is directed to apharmaceutical composition comprising pemetrexed at an initialconcentration of 10 to 50 mg/mL and a non-aqueous solvent present at aconcentration less than 0.30 ml/mL, the composition comprises no morethan 8% w/w total impurities after storage at a temperature of 2° C. to8° C. for at least 24 hours.

In further embodiments, the invention is directed to a pharmaceuticalcomposition comprising 25 mg/mL pemetrexed, 250 μL/mL propylene glycol,and water, the composition comprises no more than 8% w/w totalimpurities after storage at a temperature of 2° C. to 8° C. for at least24 hours.

Additional embodiments of the invention include:

-   1. A pharmaceutical composition comprising:    -   a) pemetrexed and    -   b) a non-aqueous solvent present at less than 0.30 mL/mL;    -   wherein upon dilution with a pharmaceutically acceptable diluent        to an initial dosage concentration of pemetrexed, the        composition comprises at least 90% of the initial dosage        concentration of pemetrexed after storage at a temperature of        2° C. to 8° C. for at least 12 hours.-   2. The pharmaceutical composition of embodiment 1 wherein the    composition retains at least 90% of the initial dosage concentration    of pemetrexed upon dilution and storage for a period selected from:    -   a) at least 24 hours, and    -   b) at least 48 hours.-   3. The pharmaceutical composition of embodiment 1 wherein the    composition retains at least 95% of the initial dosage concentration    of pemetrexed upon dilution and storage for a period selected from:    -   a) at least 12 hours,    -   b) at least 24 hours, and    -   c) at least 48 hours.-   4. The pharmaceutical composition of embodiment 1 wherein the    composition retains at least 98% of the initial dosage concentration    of pemetrexed upon dilution and storage for a period selected from:    -   a) at least 12 hours,    -   b) at least 24 hours, and    -   c) at least 48 hours.-   5. The pharmaceutical composition of embodiment 1 wherein the    pharmaceutically acceptable diluent is selected from the group    consisting of normal saline, water for injection, 5% dextrose in    water, Ringer's Injection, and Lactated Ringer's Injection.-   6. The pharmaceutical composition of embodiment 1 comprising 10 to    50 mg/mL pemetrexed.-   7. The pharmaceutical composition of embodiment 6 comprising 25    mg/mL pemetrexed.-   8. The pharmaceutical formulation of embodiment 1 wherein the    non-aqueous solvent is selected from the group consisting of    propylene glycol, alcohol, polyethylene glycol, or combinations    thereof.-   9. The pharmaceutical formulation of embodiment 8 wherein the    non-aqueous solvent is propylene glycol.-   10. The pharmaceutical formulation of embodiment 9 wherein propylene    glycol is present at 250 μL/mL.-   11. The pharmaceutical composition of embodiment 1 comprising at    least 0.50 mL/mL water.-   12. The pharmaceutical composition of embodiment 1 wherein the    pemetrexed is in the form of pemetrexed diacid.-   13. The pharmaceutical composition of embodiment 1 wherein the    pemetrexed is in the form of pemetrexed disodium.-   14. The pharmaceutical composition of embodiment 1 substantially    free of an anti-oxidant.-   15. A pharmaceutical composition comprising    -   a) 25 mg/mL pemetrexed, and    -   b) propylene glycol at 250 μL/mL    -   c) water    -   wherein upon dilution with a pharmaceutically acceptable diluent        to an initial dosage concentration of pemetrexed, the        composition comprises at least 90% of the initial dosage        concentration of pemetrexed after storage at a temperature of        2° C. to 8° C. for at least 24 hours.-   16. The pharmaceutical composition of embodiment 15 wherein upon    dilution with a pharmaceutically acceptable diluent to an initial    dosage concentration of pemetrexed, the composition comprises at    least 90% of the initial dosage concentration of pemetrexed after    storage at a temperature of 2° C. to 8° C. for at least 48 hours.-   17. A pharmaceutical composition comprising:    -   a) pemetrexed at an initial concentration of 10 to 50 mg/mL and    -   b) a non-aqueous solvent present at less than 0.30 mL/mL,    -   wherein the composition comprises at least 90% of the initial        pemetrexed concentration after storage at a temperature of 2° C.        to 8° C. for at least 12 months.-   18. The pharmaceutical composition of embodiment 17 wherein the    composition comprises at least 90% of the initial pemetrexed    concentration after storage for a period selected from:    -   a) at least 18 months, and    -   b) at least 24 months.-   19. The pharmaceutical composition of embodiment 17 wherein the    composition comprises at least 95% of the initial pemetrexed    concentration after storage for a period selected from:    -   a) at least 12 months,    -   b) at least 18 months, and    -   c) at least 24 months.-   20. The pharmaceutical composition of embodiment 17 wherein the    composition comprises at least 98% of the initial pemetrexed    concentration after storage for a period selected from:    -   a) at least 12 months,    -   b) at least 18 months, and    -   c) at least 24 months.-   21. The pharmaceutical composition of embodiment 17 having an    initial pemetrexed concentration of 25 mg/mL.-   22. The pharmaceutical formulation of embodiment 17 wherein the    non-aqueous solvent is selected from the group consisting of    propylene glycol, alcohol, polyethylene glycol, or combinations    thereof.-   23. The pharmaceutical formulation of embodiment 22 wherein the    non-aqueous solvent is propylene glycol.-   24. The pharmaceutical formulation of embodiment 23 wherein    propylene glycol is present at 250 μL/mL.-   25. The pharmaceutical composition of embodiment 17 comprising at    least 0.50 mL/mL water.-   26. The pharmaceutical composition of embodiment 17 wherein the    pemetrexed is in the form of pemetrexed diacid.-   27. The pharmaceutical composition of embodiment 17 wherein the    pemetrexed is in the form of pemetrexed disodium.-   28. The pharmaceutical composition of embodiment 17 substantially    free of an anti-oxidant.-   29. A pharmaceutical composition comprising    -   a) an initial pemetrexed concentration of 25 mg/mL,    -   b) propylene glycol at 250 μL/mL, and    -   c) water;    -   wherein the composition comprises at least 90% of the initial        pemetrexed concentration after storage at a temperature of 2° C.        to 8° C. for at least 12 months.-   30. The pharmaceutical composition of embodiment 29 wherein the    composition comprises at least 90% of the initial pemetrexed    concentration after storage at a temperature of 2° C. to 8° C. for    at least 24 months.-   31. A pharmaceutical composition comprising:    -   a) pemetrexed and    -   b) a non-aqueous solvent present at less than 0.30 mL/mL,    -   wherein upon dilution with a pharmaceutically acceptable diluent        to an initial dosage concentration of pemetrexed the composition        comprises no more than 8% w/w total impurities after storage at        a temperature of 2° C. to 8° C. for at least 12 hours.-   32. The pharmaceutical composition of embodiment 31 wherein the    composition comprises no more than 8% w/w total impurities after    dilution and storage for a period selected from:    -   a) at least 24 hours, and    -   b) at least 48 hours.-   33. The pharmaceutical composition of embodiment 31 wherein the    composition comprises no more than 5% w/w total impurities after    dilution and storage for a period selected from:    -   a) at least 12 hours,    -   b) at least 24 hours, and    -   c) at least 48 hours.-   34. The pharmaceutical composition of embodiment 31 wherein the    composition comprises no more than 2% w/w total impurities after    dilution and storage for a period selected from:    -   a) at least 12 hours,    -   b) at least 24 hours, and    -   c) at least 48 hours.-   35. The pharmaceutical composition of embodiment 31 wherein the    pharmaceutically acceptable diluent is selected from the group    consisting of normal saline, water for injection, 5% dextrose in    water, Ringer's Injection, and Lactated Ringer's Injection.-   36. The pharmaceutical composition of embodiment 31 comprising 10 to    50 mg/mL pemetrexed.-   37. The pharmaceutical composition of embodiment 36 comprising 25    mg/mL pemetrexed.-   38. The pharmaceutical formulation of embodiment 31 wherein the    non-aqueous solvent is selected from the group consisting of    propylene glycol, alcohol, polyethylene glycol, or combinations    thereof.-   39. The pharmaceutical formulation of embodiment 38 wherein the    non-aqueous solvent is propylene glycol.-   40. The pharmaceutical formulation of embodiment 39 wherein    propylene glycol is present at 250 μL/mL.-   41. The pharmaceutical composition of embodiment 31 comprising at    least 0.50 mL/mL water.-   42. The pharmaceutical composition of embodiment 31 wherein the    pemetrexed is in the form of pemetrexed diacid.-   43. The pharmaceutical composition of embodiment 31 wherein the    pemetrexed is in the form of pemetrexed disodium.-   44. The pharmaceutical composition of embodiment 31 substantially    free of an anti-oxidant.-   45. A pharmaceutical composition comprising    -   a) 25 mg/mL pemetrexed,    -   b) propylene glycol at 250 μL/mL, and    -   c) water;    -   wherein upon dilution with a pharmaceutically acceptable diluent        to an initial dosage concentration of pemetrexed the composition        comprises no more than 8% w/w total impurities after storage at        a temperature of 2° C. to 8° C. for at least 24 hours.-   46. The pharmaceutical composition of embodiment 45 wherein upon    dilution with a pharmaceutically acceptable diluent to an initial    dosage concentration of pemetrexed the composition comprises no more    than 8% w/w total impurities after storage at a temperature of 2° C.    to 8° C. for at least 48 hours.-   47. A pharmaceutical composition comprising:    -   a) pemetrexed at an initial concentration of 10 to 50 mg/mL and    -   b) a non-aqueous solvent present at less than 0.30 mL/mL,    -   wherein the composition comprises no more than 8% w/w total        impurities after storage at a temperature of 2° C. to 8° C. for        at least 12 months.-   48. The pharmaceutical composition of embodiment 47 wherein the    composition comprises no more than 8% w/w total impurities after    storage for a period selected from:    -   a) at least 18 months, and    -   b) at least 24 months.-   49. The pharmaceutical composition of embodiment 47 wherein the    composition comprises no more than 5% w/w total impurities after    storage for a period selected from:    -   a) at least 12 months,    -   b) at least 18 months, and    -   c) at least 24 months.-   50. The pharmaceutical composition of embodiment 47 wherein the    composition comprises no more than 2% w/w total impurities after    storage for a period selected from:    -   a) at least 12 months,    -   b) at least 18 months, and    -   c) at least 24 months.-   51. The pharmaceutical composition of embodiment 47 comprising 25    mg/mL pemetrexed.-   52. The pharmaceutical formulation of embodiment 47 wherein the    non-aqueous solvent is selected from the group consisting of    propylene glycol, alcohol, polyethylene glycol, or combinations    thereof.-   53. The pharmaceutical formulation of embodiment 52 wherein the    non-aqueous solvent is propylene glycol.-   54. The pharmaceutical formulation of embodiment 53 wherein    propylene glycol is present at 250 μL/mL.-   55. The pharmaceutical composition of embodiment 47 comprising at    least 0.50 mL/mL water.-   56. The pharmaceutical composition of embodiment 47 wherein the    pemetrexed is in the form of pemetrexed diacid.-   57. The pharmaceutical composition of embodiment 47 wherein the    pemetrexed is in the form of pemetrexed disodium.-   58. The pharmaceutical composition of embodiment 47 substantially    free of an anti-oxidant.-   59. A pharmaceutical composition comprising    -   a) an initial pemetrexed concentration of 25 mg/mL,    -   b) propylene glycol at 250 μL/mL, and    -   c) water;    -   wherein the composition comprises no more than 8% w/w total        impurities after storage at a temperature of 2° C. to 8° C. for        at least 12 months.-   60. The pharmaceutical composition of embodiment 59 wherein the    composition comprises no more than 8% w/w total impurities after    storage at a temperature of 2° C. to 8° C. for at least 24 months.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1D: Depicts the effect of propylene glycol (PG) on thestability of certain pemetrexed formulations.

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. In the event that there is aplurality of definitions for a term used herein, those definitions inthis section prevail unless stated otherwise.

As used herein “single largest impurity” refers to the impurity with thelargest HPLC peak by percentage.

As used herein “initial dosage concentration of pemetrexed” refers theconcentration of pemetrexed at the time of dilution, prior to storage.

As used herein “initial pemetrexed concentration” refers to theconcentration of pemetrexed at the time of formulation, prior todilution and/or storage.

As used herein “room temperature” is about 20° C. to about 25° C.

Pemetrexed or a pharmaceutically acceptable salt thereof is present inthe compositions of the present invention at concentrations of betweenabout 10 mg/mL to about 50 mg/mL when calculated as anhydrous pemetrexeddiacid. In certain embodiments of the invention, pemetrexed is presentat about 10 mg/mL to about 40 mg/mL, at about 10 mg/mL to about 30mg/mL, at about 10 mg/mL to about 20 mg/mL, at about 20 mg/mL to about50 mg/mL, at about 20 mg/mL to about 40 mg/mL, at about 20 mg/mL toabout 30 mg/mL, at about 30 mg/mL to about 50 mg/mL, at about 30 mg/mLto about 40 mg/mL, or at about 40 mg/mL to about 50 mg/mL. In furtherembodiments of the invention, pemetrexed is available at about 10 mg/mL,about 15 mg/mL, 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35mg/mL, about 40 mg/mL, about 45 mg/mL, or at about 50 mg/mL.

Pemetrexed is present in the composition as the diacid, monoacid, apharmaceutically acceptable salt, or as combinations thereof. In certainembodiments of the invention, pemetrexed is present as pemetrexeddisodium, in further embodiments of the invention, pemetrexed is presentas pemetrexed dipotassium. In yet further embodiments of the invention,pemetrexed is present as pemetrexed meglumine. In still furtherembodiments of the invention, pemetrexed is present as pemetrexedtromethamine.

Non-Aqueous Solvents

Suitable non-aqueous solvents include, but are not limited to alcohols,ketones, esters, ethers, aromatic hydrocarbons, nitriles, aprotic polarsolvents, acidic solvents, and mixtures of any two or more thereof.Useful alcohols include, for example, methanol, ethanol, denaturedspirits, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol,polyhydroxy alcohols example glycerin, propylene glycol, polyethyleneglycol, diethylene glycol, diglycerin, triethylene glycol, tetraethyleneglycol, trimethylolpropane and the like. Useful ketones includepropanone, 2-butanone, and the like. Useful esters include, for example,ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate,t-butyl acetate, and the like. Useful ethers include, for example,dimethyl ether, diethyl ether, methyl t-butyl ether, ethyl methyl ether,diisopropyl ether, and the like. Useful aromatic hydrocarbons include,for example, and the like. Useful nitriles include acetonitrile,propionitrile, and the like. Useful aprotic polar solvents includeN,N-dimethylformide (DMF), dimethylsulfoxide (DMSO),N,N-dimethylacetamide (DMA), and the like.

In certain embodiments of the invention, the non-aqueous solvent is analcohol. In further embodiments of the invention, the non-aqueoussolvent is a polyhydroxy alcohol. In still further embodiments of theinvention, the non-aqueous solvent is propylene glycol. In yet furtherembodiments of the invention, the non-aqueous solvent is polyethyleneglycol. In particular embodiments of the invention, the non-aqueoussolvent is low molecular weight polyethylene glycol. In otherembodiments of the invention, the non-aqueous solvent is selected fromthe group consisting of polyethylene glycol 200, polyethylene glycol300, polyethylene glycol 400, or combinations thereof. In certainembodiments of the invention, more than one non-aqueous solvent ispresent, such as, but not limited to polyethylene glycol and propyleneglycol.

In certain embodiments of the invention, the non-aqueous solvent ispresent at a concentration of about 50 mg/mL to 300 mg/mL prior todilution. In further embodiments of the invention, the non-aqueoussolvent is present at about 50 mg/mL to 100 mg/mL, 50 mg/mL to 200mg/mL, 50 mg/mL to 250 mg/mL, 50 mg/mL to 300 mg/mL, 100 mg/mL to 200mg/mL, 100 mg/mL to 250 mg/mL, 100 mg/mL to 300 mg/mL, 200 mg/mL to 250mg/mL, 200 mg/mL to 300 mg/mL, or 250 mg/mL to 300 mg/mL prior todilution.

In particular embodiments, the non-aqueous solvent is present at aconcentration of no more than 30 weight percent (wt. %) of theformulation prior to dilution. In further embodiments, the non-aqueoussolvent is present at a concentration of at least 5 weight percent (wt.%) of the formulation prior to dilution. In certain embodiments of theinvention the non-aqueous solvent is present at 5-30 weight percent (wt.%) of the formulation prior to dilution. In particular embodiments ofthe invention the non-aqueous solvent is present at about 10-30 wt. %,15-30 wt. %, 20-30 wt. %, 25-30 wt. %, 5-28%, 10-28 wt. %, 15-28 wt. %,20-28 wt. %, 25-28 wt. %, 5-25%, 10-25 wt. %, 15-25 wt. %, 20-25 wt. %,25-28 wt. %, 5-20%, 10-20 wt. %, 15-20 wt. %, 5-15%, 10-15 wt. %, or5-10 wt % prior to dilution.

In particular embodiments, the non-aqueous solvent is present at aconcentration of no more than 300 μL/mL prior to dilution. In furtherembodiments, the non-aqueous solvent is present at a concentration of atleast 50 μL/mL prior to dilution. In certain embodiments of theinvention, the non-aqueous solvent is present at a concentration ofabout 50 μL/mL to 300 μL/mL. In further embodiments of the invention,the non-aqueous solvent is present at about 50 μL/mL to 100 μL/mL, 50μL/mL to 200 μL/mL, 50 μL/mL to 250 μL/mL, 50 μL/mL to 275 μL/mL, 50μL/mL to 300 μL/mL, 100 μL/mL to 200 μL/mL, 100 μL/mL to 250 μL/mL, 100μL/mL to 275 μL/mL, 100 μL/mL to 300 μL/mL, 200 μL/mL to 250 μL/mL, 200μL/mL to 300 μL/mL, or 250 μL/mL to 300 μL/mL prior to dilution.

In certain embodiments, water is present at a concentration of at leastabout 500 μL/mL prior to dilution. In other embodiments of theinvention, water is present at a concentration of at least about 600μL/mL, 750 μL/mL, or 950 μL/mL prior to dilution. In further embodimentsof the invention, water is present at a concentration of about 500 μL/mLto 950 μL/mL prior to dilution. In still further embodiments of theinvention, water is present at about 500 μL/mL to 800 μL/mL, 500 μL/mLto 700 μL/mL, 500 μL/mL to 600 L/mL, 600 μL/mL to 750 μL/mL, 600 μL/mLto 800 μL/mL, 600 μL/mL to 950 μL/mL, 700 μL/mL to 800 μL/mL, 700 μL/mLto 950 L/mL, or 750 μL/mL to 950 μL/mL prior to dilution.

In particular embodiments, water is present at a concentration of atleast about 50 wt. % of the formulation prior to dilution. In furtherembodiments, water is present at a concentration of at least about 60wt. %, 75 w t %, or 95 wt. % prior to dilution. In certain embodimentsof the invention water is present at a concentration of at least about50-95 wt. % prior to dilution. of the invention water is present at aconcentration of at least about 50-60 wt. %, 50-70 wt. %, 50-80 wt. %,60-70 wt. %, 60-80 wt. %, 60-95 wt. %, 70-80 wt. %, or 70-95 wt. % priorto dilution

In certain embodiments of the invention the formulation is substantiallyfree of anti-oxidants and/or amino acids. In particular embodiments ofthe invention, the formulation is substantially free of anti-oxidants.In further embodiments of the invention, the formulation issubstantially free of chelating agents. As used herein, substantiallyfree of anti-oxidants, amino acids, and/or chelating agents means theformulation does not comprise one or more anti-oxidants, amino acids,and/or chelating agents, at a concentration sufficient to have astabilizing effect.

In particular embodiments, the formulation is substantially free ofadditives selected from the group consisting of ascorbic acid andderivatives, tocopherols and derivatives, propyl gallate, thioglycerol,lactobionic acid, methionine, tertiary butylhydroquinone (TBHQ),butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodiumformaldehyde sulfoxylate, sodium hydrogen sulfite,Eethylenediaminetetraacetic acid (EDTA) and derivatives,monoethanolamine gentisate, glutathione, propionic acid, acetone sodiumbisulfite, sodium dithionite, citric acid and derivatives, tribasic (trisodium citrate dihydrate), or suitable mixtures thereof. As used herein,substantially free means the formulation does not comprise one or moreadditives listed above at a concentration sufficient to have astabilizing effect.

In particular embodiments of the invention, the formulation comprisestromethamine. In certain embodiments of the invention, the formulationcomprises about 12 to 24 mg/mL tromethamine. In further embodiments ofthe invention, the formulation comprises about 12 to 14 mg/mLtromethamine, about 12 to 16 mg/mL tromethamine, about 14 to 16 mg/mLtromethamine, about 14 to 18 mg/mL tromethamine, about 16 to 18 mg/mLtromethamine, about 16 to 20 mg/mL tromethamine, about 17 to 19 mg/mLtromethamine, about 17 to 21 mg/mL tromethamine, about 18 to 20 mg/mLtromethamine, about 18 to 22 mg/mL tromethamine, about 20 to 22 mg/mLtromethamine, about 20 to 24 mg/mL tromethamine, or about 22 to 24 mg/mLtromethamine. In yet further embodiments of the invention, theformulation comprises about 18 mg/mL tromethamine.

In certain embodiments of the invention, the formulation is notsubstantially degraded after storage at room temperature for at leastabout 6 months. In particular embodiments of the invention, theformulation is not substantially degraded after storage at roomtemperature for at least about 1 year. In further embodiments of theinvention, the formulation is not substantially degraded after storageat room temperature for at least about 18 months. In still furtherembodiments of the invention, the formulation is not substantiallydegraded after storage at room temperature for at least about 2 years.

In further embodiments of the invention, the formulation is notsubstantially degraded after storage at 2-8° C. for at least about 6months. In certain embodiments of the invention, the formulation is notsubstantially degraded after storage at 2-8° C. for at least about 1year. In further embodiments of the invention, the formulation is notsubstantially degraded after storage at 2-8° C. for at least about 18months. In still further embodiments of the invention, the formulationis not substantially degraded after storage at 2-8° C. for at leastabout 2 years.

In other embodiments of the invention, the formulation comprises no morethan about 10% w/w impurities, no more than about 8% w/w impurities, nomore than about 6% w/w impurities, no more than about 5% w/w impurities,no more than about 4% w/w impurities, no more than about 3.5% w/wimpurities, no more than about 3% w/w impurities, no more than about2.5% w/w impurities, no more than about 2% w/w impurities, no more thanabout 1.5% w/w impurities, no more than about 1% w/w impurities, no morethan about 0.5% w/w impurities, no more than about 0.2% w/w impurities,no more than about 0.1% w/w impurities, after storage at roomtemperature for at least about 6 months, about 12 months, about 18,months, or about 24 months.

In further embodiments of the invention, the formulation comprises nomore than about 10% w/w impurities, no more than about 8% w/wimpurities, no more than about 6% w/w impurities, no more than about 5%w/w impurities, no more than about 4% w/w impurities, no more than about3.5% w/w impurities, no more than about 3% w/w impurities, no more thanabout 2.5% w/w impurities, no more than about 2% w/w impurities, no morethan about 1.5% w/w impurities, no more than about 1% w/w impurities, nomore than about 0.5% w/w impurities, no more than about 0.2% w/wimpurities, no more than about 0.1% w/w impurities, after storage at2-8° C. for at least about 6 months, about 12 months, about 18, months,or about 24 months.

In still further embodiments of the invention, the formulation comprisesno more than about 10% w/w of the single largest impurity, no more thanabout 8% w/w of the single largest impurity, no more than about 6% w/wof the single largest impurity, no more than about 5% w/w of the singlelargest impurity, no more than about 4% w/w of the single largestimpurity, no more than about 3.5% w/w of the single largest impurity, nomore than about 3% w/w of the single largest impurity, no more thanabout 2.5% w/w of the single largest impurity, no more than about 2% w/wof the single largest impurity, no more than about 1.5% w/w of thesingle largest impurity, no more than about 1% w/w of the single largestimpurity, no more than about 0.5% w/w of the single largest impurity, nomore than about 0.2% w/w of the single largest impurity, no more thanabout 0.1% w/w of the single largest impurity, after storage at roomtemperature for at least about 6 months, about 12 months, about 18,months, or about 24 months.

In yet further embodiments of the invention, the formulation comprisesno more than about 10% w/w of the single largest impurity, no more thanabout 8% w/w of the single largest impurity, no more than about 6% w/wof the single largest impurity, no more than about 5% w/w of the singlelargest impurity, no more than about 4% w/w of the single largestimpurity, no more than about 3.5% w/w of the single largest impurity, nomore than about 3% w/w of the single largest impurity, no more thanabout 2.5% w/w of the single largest impurity, no more than about 2% w/wof the single largest impurity, no more than about 1.5% w/w of thesingle largest impurity, no more than about 1% w/w of the single largestimpurity, no more than about 0.5% w/w of the single largest impurity, nomore than about 0.2% w/w of the single largest impurity, no more thanabout 0.1% w/w of the single largest impurity, after storage at 2-8° C.for at least about 6 months, about 12 months, about 18, months, or about24 months.

In particular embodiments of the invention, the formulation retains atleast about 85% of its initial pemetrexed concentration, at least about90% of its initial pemetrexed concentration, the formulation retains atleast about 92% of its initial pemetrexed concentration, at least about95% of its initial pemetrexed concentration, the formulation retains atleast about 97% of its initial pemetrexed concentration, at least about98% of its initial pemetrexed concentration, at least about 99% of itsinitial pemetrexed concentration, at least about 99.5% of its initialpemetrexed concentration, after storage at room temperature for at leastabout 6 months, about 12 months, about 18, months, or about 24 months.

In further embodiments of the invention, the formulation retains atleast about 85% of its initial pemetrexed concentration, at least about90% of its initial pemetrexed concentration, the formulation retains atleast about 92% of its initial pemetrexed concentration, at least about95% of its initial pemetrexed concentration, the formulation retains atleast about 97% of its initial pemetrexed concentration, at least about98% of its initial pemetrexed concentration, at least about 99% of itsinitial pemetrexed concentration, at least about 99.5% of its initialpemetrexed concentration, after storage at 2-8° C. for at least about 6months, about 12 months, about 18, months, or about 24 months.

In certain embodiments of the invention, the formulation is furtherdiluted in a pharmaceutically acceptable diluent. Suitable diluentsinclude, but are not limited to saline, dextrose, water, Ringer'sInjection, and Lactated Ringer's Injection. In certain embodiments ofthe invention, the formulation can be diluted in a calcium containingdiluent, such as Ringer's Injection or Lactated Ringer's Injection.

In particular embodiments of the invention, the formulation is dilutedin a pharmaceutically acceptable diluent to a suitable initial dosageconcentration of pemetrexed. In certain embodiments of the invention theinitial dosage concentration of pemetrexed is based on various factors,such as, but not limited to the patient's weight, age, and condition aswell as the volume of diluent and can be determined by a practitioner orone of skill in the art. In further embodiments, pemetrexed is dilutedto an initial dosage concentration and can be further diluted prior toadministration.

In other embodiments of the invention, the formulation retains at leastabout 85% of its initial dosage concentration of pemetrexed, at leastabout 90% of its initial dosage concentration of pemetrexed, at leastabout 92% of its initial dosage concentration of pemetrexed, at leastabout 95% of its initial dosage concentration of pemetrexed, at leastabout 97% of its initial dosage concentration of pemetrexed, at leastabout 98% of its initial dosage concentration of pemetrexed, at leastabout 99% of its initial dosage concentration of pemetrexed, at leastabout 99.5% of its initial dosage concentration of pemetrexed, afterdilution and storage at about 2° C. to about 8° C. for at least about 12hours.

In still other embodiments of the invention, the formulation retains atleast about 85% of its initial dosage concentration of pemetrexed, atleast about 90% of its initial dosage concentration of pemetrexed, atleast about 92% of its initial dosage concentration of pemetrexed, atleast about 95% of its initial dosage concentration of pemetrexed, atleast about 97% of its initial dosage concentration of pemetrexed, atleast about 98% of its initial dosage concentration of pemetrexed, atleast about 99% of its initial dosage concentration of pemetrexed, atleast about 99.5% of its initial dosage concentration of pemetrexed,after dilution and storage at about 2° C. to about 8° C. for at leastabout 24 hours.

In yet other embodiments of the invention, the formulation retains atleast about 85% of its initial dosage concentration of pemetrexed, atleast about 90% of its initial dosage concentration of pemetrexed, atleast about 92% of its initial dosage concentration of pemetrexed, atleast about 95% of its initial dosage concentration of pemetrexed, atleast about 97% of its initial dosage concentration of pemetrexed, atleast about 98% of its initial dosage concentration of pemetrexed, atleast about 99% of its initial dosage concentration of pemetrexed, atleast about 99.5% of its initial dosage concentration of pemetrexed,after dilution and storage at about 2° C. to about 8° C. for at leastabout 48 hours.

In further embodiments of the invention, the formulation comprises nomore than about 10% w/w impurities, no more than about 8% w/wimpurities, no more than about 6% w/w impurities, no more than about 5%w/w impurities, no more than about 4% w/w impurities, no more than about3.5% w/w impurities, no more than about 3% w/w impurities, no more thanabout 2.5% w/w impurities, no more than about 2% w/w impurities, no morethan about 1.5% w/w impurities, no more than about 1% w/w impurities, nomore than about 0.5% w/w impurities, no more than about 0.2% w/wimpurities, no more than about 0.1% w/w impurities, after dilution andstorage at about 2° C. to about 8° C. for at least about 12 hours.

In other embodiments of the invention, the formulation comprises no morethan about 10% w/w impurities, no more than about 8% w/w impurities, nomore than about 6% w/w impurities, no more than about 5% w/w impurities,no more than about 4% w/w impurities, no more than about 3.5% w/wimpurities, no more than about 3% w/w impurities, no more than about2.5% w/w impurities, no more than about 2% w/w impurities, no more thanabout 1.5% w/w impurities, no more than about 1% w/w impurities, no morethan about 0.5% w/w impurities, no more than about 0.2% w/w impurities,no more than about 0.1% w/w impurities, after dilution and storage atabout 2° C. to about 8° C. for at least about 24 hours.

In yet other embodiments of the invention, the formulation comprises nomore than about 10% w/w impurities, no more than about 8% w/wimpurities, no more than about 6% w/w impurities, no more than about 5%w/w impurities, no more than about 4% w/w impurities, no more than about3.5% w/w impurities, no more than about 3% w/w impurities, no more thanabout 2.5% w/w impurities, no more than about 2% w/w impurities, no morethan about 1.5% w/w impurities, no more than about 1% w/w impurities, nomore than about 0.5% w/w impurities, no more than about 0.2% w/wimpurities, no more than about 0.1% w/w impurities, after dilution andstorage at about 2° C. to about 8° C. for at least about 48 hours.

In still other embodiments of the invention, the formulation comprisesno more than about 10% w/w of the single largest impurity, no more thanabout 8% w/w of the single largest impurity, no more than about 6% w/wof the single largest impurity, no more than about 5% w/w of the singlelargest impurity, no more than about 4% w/w of the single largestimpurity, no more than about 3.5% w/w of the single largest impurity, nomore than about 3% w/w of the single largest impurity, no more thanabout 2.5% w/w of the single largest impurity, no more than about 2% w/wof the single largest impurity, no more than about 1.5% w/w of thesingle largest impurity, no more than about 1% w/w of the single largestimpurity, no more than about 0.5% w/w of the single largest impurity, nomore than about 0.2% w/w of the single largest impurity, no more thanabout 0.1% w/w of the single largest impurity, after dilution andstorage at about 2° C. to about 8° C. for at least about 12 hours.

In further embodiments of the invention, the formulation comprises nomore than about 10% w/w of the single largest impurity, no more thanabout 8% w/w of the single largest impurity, no more than about 6% w/wof the single largest impurity, no more than about 5% w/w of the singlelargest impurity, no more than about 4% w/w of the single largestimpurity, no more than about 3.5% w/w of the single largest impurity, nomore than about 3% w/w of the single largest impurity, no more thanabout 2.5% w/w of the single largest impurity, no more than about 2% w/wof the single largest impurity, no more than about 1.5% w/w of thesingle largest impurity, no more than about 1% w/w of the single largestimpurity, no more than about 0.5% w/w of the single largest impurity, nomore than about 0.2% w/w of the single largest impurity, no more thanabout 0.1% w/w of the single largest impurity, after dilution andstorage at about 2° C. to about 8° C. for at least about 24 hours.

In still further embodiments of the invention, the formulation comprisesno more than about 10% w/w of the single largest impurity, no more thanabout 8% w/w of the single largest impurity, no more than about 6% w/wof the single largest impurity, no more than about 5% w/w of the singlelargest impurity, no more than about 4% w/w of the single largestimpurity, no more than about 3.5% w/w of the single largest impurity, nomore than about 3% w/w of the single largest impurity, no more thanabout 2.5% w/w of the single largest impurity, no more than about 2% w/wof the single largest impurity, no more than about 1.5% w/w of thesingle largest impurity, no more than about 1% w/w of the single largestimpurity, no more than about 0.5% w/w of the single largest impurity, nomore than about 0.2% w/w of the single largest impurity, no more thanabout 0.1% w/w of the single largest impurity, after dilution andstorage at about 2° C. to about 8° C. for at least about 48 hours.

In other embodiments of the invention, the formulation retains at leastabout 85% of its initial dosage concentration of pemetrexed, at leastabout 90% of its initial dosage concentration of pemetrexed, at leastabout 92% of its initial dosage concentration of pemetrexed, at leastabout 95% of its dosage concentration of pemetrexed, at least about 97%of its dosage concentration of pemetrexed, at least about 98% of itsdosage concentration of pemetrexed, at least about 99% of its dosageconcentration of pemetrexed, at least about 99.5% of its dosageconcentration of pemetrexed, after dilution and storage at roomtemperature for at least about 12 hours.

In still other embodiments of the invention, the formulation retains atleast about 85% of its initial dosage concentration of pemetrexed, atleast about 90% of its initial dosage concentration of pemetrexed, atleast about 92% of its initial dosage concentration of pemetrexed, atleast about 95% of its dosage concentration of pemetrexed, at leastabout 97% of its dosage concentration of pemetrexed, at least about 98%of its dosage concentration of pemetrexed, at least about 99% of itsdosage concentration of pemetrexed, at least about 99.5% of its dosageconcentration of pemetrexed, after dilution and storage at roomtemperature for at least about 24 hours.

In yet other embodiments of the invention, the formulation retains atleast about 85% of its initial dosage concentration of pemetrexed, atleast about 90% of its initial dosage concentration of pemetrexed, atleast about 92% of its initial dosage concentration of pemetrexed, atleast about 95% of its initial pemetrexed concentration, the formulationretains at least about 97% of its initial pemetrexed concentration, atleast about 98% of its initial pemetrexed concentration, at least about99% of its initial pemetrexed concentration, at least about 99.5% of itsinitial pemetrexed concentration, after dilution and storage at aboutroom temperature for at least about 48 hours.

In further embodiments of the invention, the formulation comprises nomore than about 10% w/w impurities, no more than about 8% w/wimpurities, no more than about 6% w/w impurities, no more than about 5%w/w impurities, no more than about 4% w/w impurities, no more than about3.5% w/w impurities, no more than about 3% w/w impurities, no more thanabout 2.5% w/w impurities, no more than about 2% w/w impurities, no morethan about 1.5% w/w impurities, no more than about 1% w/w impurities, nomore than about 0.5% w/w impurities, no more than about 0.2% w/wimpurities, no more than about 0.1% w/w impurities, after dilution andstorage at room temperature for at least about 12 hours.

In other embodiments of the invention, the formulation comprises no morethan about 10% w/w impurities, no more than about 8% w/w impurities, nomore than about 6% w/w impurities, no more than about 5% w/w impurities,no more than about 4% w/w impurities, no more than about 3.5% w/wimpurities, no more than about 3% w/w impurities, no more than about2.5% w/w impurities, no more than about 2% w/w impurities, no more thanabout 1.5% w/w impurities, no more than about 1% w/w impurities, no morethan about 0.5% w/w impurities, no more than about 0.2% w/w impurities,no more than about 0.1% w/w impurities, after dilution and storage atroom temperature for at least about 24 hours.

In yet other embodiments of the invention, the formulation comprises nomore than about 10% w/w impurities, no more than about 8% w/wimpurities, no more than about 6% w/w impurities, no more than about 5%w/w impurities, no more than about 4% w/w impurities, no more than about3.5% w/w impurities, no more than about 3% w/w impurities, no more thanabout 2.5% w/w impurities, no more than about 2% w/w impurities, no morethan about 1.5% w/w impurities, no more than about 1% w/w impurities, nomore than about 0.5% w/w impurities, no more than about 0.2% w/wimpurities, no more than about 0.1% w/w impurities, after dilution andstorage at room temperature for at least about 48 hours.

In further embodiments of the invention, the formulation comprises nomore than about 10% w/w of the single largest impurity, no more thanabout 8% w/w of the single largest impurity, no more than about 6% w/wof the single largest impurity, no more than about 5% w/w of the singlelargest impurity, no more than about 4% w/w of the single largestimpurity, no more than about 3.5% w/w of the single largest impurity, nomore than about 3% w/w of the single largest impurity, no more thanabout 2.5% w/w of the single largest impurity, no more than about 2% w/wof the single largest impurity, no more than about 1.5% w/w of thesingle largest impurity, no more than about 1% w/w of the single largestimpurity, no more than about 0.5% w/w of the single largest impurity, nomore than about 0.2% w/w of the single largest impurity, no more thanabout 0.1% w/w of the single largest impurity, after dilution andstorage at room temperature for at least about 12 hours.

In yet further embodiments of the invention, the formulation comprisesno more than about 10% w/w of the single largest impurity, no more thanabout 8% w/w of the single largest impurity, no more than about 6% w/wof the single largest impurity, no more than about 5% w/w of the singlelargest impurity, no more than about 4% w/w of the single largestimpurity, no more than about 3.5% w/w of the single largest impurity, nomore than about 3% w/w of the single largest impurity, no more thanabout 2.5% w/w of the single largest impurity, no more than about 2% w/wof the single largest impurity, no more than about 1.5% w/w of thesingle largest impurity, no more than about 1% w/w of the single largestimpurity, no more than about 0.5% w/w of the single largest impurity, nomore than about 0.2% w/w of the single largest impurity, no more thanabout 0.1% w/w of the single largest impurity, after dilution andstorage at room temperature for at least about 24 hours.

In still further embodiments of the invention, the formulation comprisesno more than about 10% w/w of the single largest impurity, no more thanabout 8% w/w of the single largest impurity, no more than about 6% w/wof the single largest impurity, no more than about 5% w/w of the singlelargest impurity, no more than about 4% w/w of the single largestimpurity, no more than about 3.5% w/w of the single largest impurity, nomore than about 3% w/w of the single largest impurity, no more thanabout 2.5% w/w of the single largest impurity, no more than about 2% w/wof the single largest impurity, no more than about 1.5% w/w of thesingle largest impurity, no more than about 1% w/w of the single largestimpurity, no more than about 0.5% w/w of the single largest impurity, nomore than about 0.2% w/w of the single largest impurity, no more thanabout 0.1% w/w of the single largest impurity, after dilution andstorage at a room temperature for at least about 48 hours.

In particular embodiments of the invention the formulation is in a vialwith a headspace oxygen concentration of less than about 20 v/v %, 18v/v %, 16 v/v %, 14 v/v %, 12 v/v %, 10 v/v %, 8 v/v %, 6 v/v %, 5 v/v%, 4 v/v %, 3 v/v %, 2 v/v %, or 1 v/v % oxygen.

In certain embodiments of the invention, the formulation is in asingle-dose vial. In further embodiments of the invention, theformulation is in a multi-dose vial. In yet further embodiments of theinvention, the formulation is in a multi-dose vial intended for use bythe same patient. In still further embodiments of the invention, theformulation is in a multi-dose vial intended for use by differentpatients.

In another embodiment, the invention relates to a method ofadministering pemetrexed to a patient in need thereof comprisingadministering an effective amount of a formulation as described herein.In a further embodiment, the invention relates to a method ofadministering pemetrexed to a patient in need thereof comprisingadministering an effective amount of a formulation comprising pemetrexedand a non-aqueous solvent present at less than 30 wt %. In a furtherembodiment, the invention relates to a method of administeringpemetrexed to a patient in need thereof comprising administering aneffective amount of a formulation comprising pemetrexed and propyleneglycol wherein the propylene glycol is present at 5-30 wt %.

EXAMPLES Example 1: Effect of Non-Aqueous Solvents on PemetrexedStability

Formulations as described in Table 1 were prepared as follows:

Water for Injection, a suitable base solution (0.1-1 N NaOH or KOH), andcitric acid, if present, were combined and mixed to yield a visuallyuniform mixture. Pemetrexed diacid was incrementally added to themixture under continuous agitation, and the resulting homogenoussuspension was agitated until all solids were completely dissolved. ThepH of the solution was adjusted to about 7.4-7.6. Propylene glycol, ifpresent, was then added to the pemetrexed solution, and the mixture wasagitated until a visually uniform mixture was obtained. The pH of thesolution was adjusted to 7.4-7.6.

B C F I Pemetrexed 25 25 25 25 (diacid) (mg/mL) Citric Acid • 13.2 13.2— — H₂O (mg/mL) Propylene 250 — — 250 Glycol (μL/mL) NaOH qs to qs to qsto qs to pH 7.5 pH 7.5 pH 7.5 pH 7.5 Hydrochloric Acid qs to qs to qs toqs to pH 7.5 pH 7.5 pH 7.5 pH 7.5 WFI qs qs qs qs

The stability of Formulations B, C, F, and I was tested underaccelerated conditions at 60° C. and 40° C./75% RH over the course ofseveral days. Samples were taken at various time points and diluted withHPLC diluents (60:40 (v/v, Water:ACN)) prior to testing. Impurities weremeasured by HPLC.

The results are shown in Tables 2A-2D and FIGS. 1A-1D.

TABLE 2A Single Largest Impurity (% w/w) after storage at 60° C. B C F IInitial 0.09 0.15 0.10 0.07 1 day 0.61 1.26 1.00 0.56 2 day 1.16 2.561.97 1.04 3 day 1.68 4.01 2.91 1.50

TABLE 2B Total Impurities (% w/w) after storage at 60° C. Total ImpurityB C F I Initial 0.69 0.92 0.74 0.70 1 day 1.50 2.35 2.02 1.39 2 day 2.203.93 3.31 2.04 3 day 2.86 5.63 4.54 2.65

TABLE 2C Single Largest Impurity (% w/w) after storage at 40° C./75% RHRRT 0.87 B C F I Initial 0.09  0.15 0.10 0.07 2 days 1.70  6.36 3.361.33 4 days 3.29 13.44 9.24 2.35

TABLE 2D Total Impurities after (% w/w) storage at 40° C./75% RH TotalImpurity B C F I Initial 0.69  0.92  0.74 0.70 2 days 3.63 11.75  7.282.75 4 days 6.05 20.94 16.71 4.31

The long term stability, real-time, and projected, of formulations B, I,and K (See Table 4, prepared as described above) were also measured.Results are shown in Table 3

TABLE 3 Long Term Stability of Pemetrexed Formulations B, I, and KSingle Projected Projected Storage Largest Total TI in SLI in Head at2-8 C. Impurity Impurities 24 M 24 M Assay space (Months) (% w/w) (%w/w) (% w/w) (% w/w) (% LC) pH oxygen Formulation B 15 0.57 4.70 7.520.91 93.6 7.59 18.1 Formulation I 15 0.31 1.70 2.72 0.50 97.8 7.50 20.9Formulation K 14 0.42 2.96 5.07 0.72 95.2 7.47 19.6

TABLE 4 Pemetrexed Formulation K Ingredient /mL Pemetrexed diacid 25.0mg Propylene Glycol 250 μL Tromethamine qs to pH 7.4-7.6 HydrochloricAcid qs to pH 7.4-7.6 Water for Injection qs to 1 mL

Example 2: Stability of Pemetrexed Formulation K after Dilution

The stability of pemetrexed for up to 48 hours after dilution ofFormulation K was evaluated. Normal saline, water for injection and 5%dextrose in water, Ringer's Injection, and Lactated Ringer's Injectionwere purchased directly and used as is. The pH of each diluent wastested and recorded in Table 6.

TABLE 6 pH of diluents Diluent pH Normal Saline (NS) 6.8 Water forInjection (WFI) 7.01 Ringer’s Injection (LR) 6.6 Lactated Ringer’sInjection (LRS) 6.5 5% Dextrose in Water (D5W) 7.5

Formulation K (25 mg/mL) was diluted to 0.15, 1.5, and 15 mg/mL in thediluents listed above. The mixtures were stored at 2-8° C. and tested at12, 24, and 48 hours for appearance, assay, impurities, and pH. A samplewas taken immediately after dilution for the time zero sample. The 0.15mg/mL samples were analyzed as is without further dilution, while the1.5 mg/mL and 15 mg/mL samples were diluted with HPLC diluents (60:40(v/v, Water:ACN)) prior to testing. Results are in Tables 6 & 7 (eachTable represents separate studies).

TABLE 6 Stability of Formulation K after dilution in Normal Saline orWater for Injection Theoretical *Percentage of Total Time Pemetrexedconc Assay Theoretical Impurity Diluents (hrs) (mg/mL) (mg/g) Pemetrexed% pH (% w/w) Bulk Solution — 25.0 24.80 99.2 7.50 0.16 NS 0 0.15 100.007.45 0.08 24 0.15 0.15 100.00 7.50 0.10 48 0.15 100.00 7.43 0.19 0 1.51.52 101.54 7.40 0.12 24 1.51 100.87 7.52 0.17 48 1.50 100.20 7.52 0.160 15 14.55 98.84 7.47 0.08 24 14.61 99.25 7.54 0.19 48 14.71 99.93 7.580.17 WFI 0 0.15 0.15 100.00 7.42 0.07 24 0.15 100.00 7.53 0.04 48 0.15100.00 7.56 0.07 0 1.5 1.50 100.20 7.30 0.14 24 1.50 100.20 7.47 0.17 481.51 100.87 7.50 0.16 0 14.60 99.18 7.52 0.14 24 15 14.40 97.82 7.580.16 48 14.70 99.86 7.59 0.11

TABLE 7 Stability of Formulation K after dilution in Ringer's Injection,Lactated Ringer's Injection, or 5% Dextrose Theoretical *Percentage ofTime Pemetrexed conc Assay Theoretical Total Diluents (hrs) (mg/mL) (%LC) Pemetrexed % pH Impurity Bulk solution — 25.0 97.6 NA 7.37 0.35 RS 00.15 95.4 97.8 7.23 0.41 12 95.8 98.2 7.62 0.40 24 95.3 97.6 7.57 0.4248 95.4 97.8 7.72 0.44 0 1.5 95.8 98.2 7.45 0.31 12 96.2 98.6 7.53 0.3424 95.1 97.4 7.46 0.36 48 95.4 97.7 7.53 0.34 0 15 97.8 100.2 7.47 0.3512 98.3 100.7 7.55 0.35 24 97.4 99.7 7.39 0.36 48 95.6 98.0 7.53 0.33LRS 0 0.15 98.5 100.9 7.54 0.47 12 98.9 101.3 7.45 0.55 24 98.5 100.97.24 0.48 48 98.8 101.2 7.68 0.45 0 1.5 98.4 100.8 7.59 0.32 12 98.1100.5 7.49 0.33 24 97.4 99.8 7.33 0.34 48 98.2 100.6 7.58 0.35 0 15 97.8100.2 7.41 0.33 12 98.3 100.7 7.58 0.32 24 98.2 100.6 7.36 0.34 48 98.7101.1 7.46 0.33 D5W 0 0.15 97.8 100.2 7.50 0.40 12 97.9 100.3 7.37 0.4624 97.7 100.1 7.34 0.58 48 97.9 100.3 7.57 0.52 0 1.5 97.0 99.4 7.390.31 12 96.6 99.0 7.62 0.33 24 97.5 99.9 7.30 0.40 48 97.2 99.6 7.530.39 0 15 97.7 100.1 7.47 0.31 12 98.0 100.3 7.61 0.34 24 97.9 100.37.40 0.32 48 98.0 100.4 7.59 0.34

The foregoing detailed description has been given for clearness ofunderstanding only and no unnecessary limitations should be understoodthere from as modifications will be obvious to those skilled in the art.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth and as follows in the scope ofthe appended claims.

The disclosures, including the claims, figures and/or drawings, of eachand every patent, patent application, and publication cited herein arehereby incorporated herein by reference in their entireties.

1-30. (canceled)
 31. A liquid pharmaceutical composition comprising:pemetrexed at a concentration of about 20 mg/mL to about 30 mg/mL; atleast about 24 mg/mL of tromethamine; citric acid; methionine; andwater, wherein the composition comprises at least 90% of said pemetrexedconcentration after storage at a temperature of 2° C. to 8° C. for atleast 12 months.
 32. The liquid pharmaceutical composition of claim 31,comprising pemetrexed at a concentration of about 25 mg/mL.
 33. Theliquid pharmaceutical composition of claim 31, wherein the pemetrexed ispemetrexed diacid, pemetrexed monoacid, a pharmaceutically acceptablesalt of pemetrexed, or a combination thereof.
 34. The liquidpharmaceutical composition of claim 31, wherein the pemetrexed ispemetrexed diacid.
 35. The liquid pharmaceutical composition of claim31, wherein the concentration of the citric acid is about 13 mg/mL. 36.The liquid pharmaceutical composition of claim 31, wherein the pH of thecomposition is from about 7.4 to about 7.6.
 37. The liquidpharmaceutical composition of claim 31, wherein the pH of thecomposition is 7.4.
 38. The liquid pharmaceutical composition of claim31, wherein the pH of the composition is 7.5.
 39. The liquidpharmaceutical composition of claim 31, wherein the pH of thecomposition is 7.6.
 40. The liquid pharmaceutical composition of claim31, wherein the composition is stored in a vial with a headspace oxygenconcentration of about 20 v/v %.
 41. The liquid pharmaceuticalcomposition of claim 31, wherein the composition comprises at least 90%of said pemetrexed concentration after storage at a temperature of 2° C.to 8° C. for at least 18 months.
 42. The liquid pharmaceuticalcomposition of claim 31, wherein the composition comprises no more thanabout 8% w/w total impurities after storing the composition at atemperature of 2° C. to 8° C. for at least 12 months.
 43. A liquidpharmaceutical composition consisting essentially of: pemetrexed at aconcentration of about 20 mg/mL to about 30 mg/mL; at least about 24mg/mL of tromethamine; citric acid; methionine; and water, wherein thecomposition comprises at least 90% of said pemetrexed concentrationafter storage at a temperature of 2° C. to 8° C. for at least 12 months.44. A liquid pharmaceutical composition consisting of: pemetrexed at aconcentration of about 20 mg/mL to about 30 mg/mL; at least about 24mg/mL of tromethamine; citric acid; methionine; and water, wherein thecomposition comprises at least 90% of said pemetrexed concentrationafter storage at a temperature of 2° C. to 8° C. for at least 12 months.45. A method of treating pleural mesothelioma or non-squamous, non-smallcell lung cancer in a patient in need thereof comprising: providing theliquid pharmaceutical composition of claim 31; diluting the liquidpharmaceutical composition with a pharmaceutically acceptable diluent toform a diluted liquid composition having a diluted pemetrexedconcentration; and intravenously administering the diluted liquidcomposition to the patient.
 46. The method of claim 45, wherein thepharmaceutically acceptable diluent is selected from the groupconsisting of saline, water for injection, 5% dextrose in water,Ringer's Injection, and Lactated Ringer's Injection.
 47. The method ofclaim 45, wherein the diluent is 5% dextrose in water.
 48. The method ofclaim 45, wherein the diluted liquid composition comprises at least 90%of said diluted pemetrexed concentration after storage at a temperatureof 2° C. to 8° C. for at least 12 hours.
 49. The method of claim 45,wherein the diluted liquid composition comprises at least 90% of saiddiluted pemetrexed concentration after storage at a temperature of 2° C.to 8° C. for at least 24 hours.
 50. The method of claim 45, wherein thediluted liquid composition comprises at least 90% of said dilutedpemetrexed concentration after storage at a temperature of 2° C. to 8°C. for at least 48 hours.